(a) Field of the Invention
This invention relates to compounds that are useful in the treatment and prevention of ulcers. More particularly, this invention relates to [(1H-benzimidazol-2-ylsulfinyl)methyl)-2-pyridinamines that inhibit gastric acid secretion and which are, therefore, useful in the treatment of peptic ulcers. The compounds of this invention directly inhibit acid secretion by parietal cells of the stomach through inhibition of (H.sup.+ +K.sup.+)-ATPase. For review, see, e.g., J. G. Spenney, "Biochemical Mechanisms of Acid Secretion by Gastric Parietal Cells," J. Clin. Gastro., 5 (Suppl. 1), 7-15 (1983). In addition, some of the compounds of this invention also exert cytoprotective activity. For review of cytoprotection, see, e.g., U.S. Pat. No. 4,359,465.
(b) Prior Art
Heterocyclylalkylsulfinylbenzimidazoles have been disclosed as gastric acid secretion inhibitors. See U.S. Pat. Nos. 4,472,409, 4,394,509, 4,337,257, 4,327,102, 4,255,431, 4,045,564, and 4,045,563; British Pat. No. 2,134,523; German Offenlegungeschrift No. 3,415,971 and Swedish Pat. No. 416649. Some heterocyclylalkylsulfinylbenzimidazoles have also been disclosed as cytoprotective agents. See U.S. Pat. No. 4,359,465. The following structure is illustrative of compounds disclosed in these patents: ##STR1## wherein R' and R" represent hydrogen, alkyl, halogen, trifluoromethyl, cyano, carboxy, hydroxy, acyl, and the like; R'" represents hydrogen, alkyl, acyl, alkoxysulfonyl, and the like; and Het represents heterocyclic groups containing at least one endocyclic (ring) nitrogen. No compound disclosed in these patents includes an exocyclic amino function attached to the Het group, a feature characteristic of the compounds of the present invention. Moreover, where the Het function is 2-pyridyl, antisecretory effects are reportedly absent when the pyridine ring is substituted at the 6-position with groups other than the amino groups of this invention. See A. Brandstrom, P. Lindberg, and U. Junggren, "Structure activity relationships of substituted benzimidazoles," Scand. J. Gastroenterol., 20 (suppl. 108), 15-22 (1985).
Heterocyclylalkylsulfinylnaphth[2,3-d]imidazoles have also been disclosed as gastric acid secretion inhibitors. See U.S. Pat. Nos. 4,248,880 and 4,182,766. The compounds disclosed in these patents are related to those illustrated the above structure, except for having a substituted naphth[2,3-d]imidazole group instead of the benzimidazole group. Similarly, other heterocyclylalkylsulfinylbenzimidazoles having a ring fused to the benzimidazole group have been disclosed as gastric acid secretion inhibitors and cytoprotective agents. See European Patent Application Nos. 130,729 and 127,763. Because of the additional ring fusions of these compounds, as well as for the same reasons stated in the preceeding paragraph, the compounds of the present invention are structurally distinguished from prior art compounds cited.
Benzylsulfinylbenzimidazoles have also been disclosed as antiulcer agents. Belgian Pat. No. 903,128. No compounds disclosed in the Belgian patent contain a pyridine ring, a feature characteristic of the compounds of this invention.
The invention relates to compounds of Formula I: ##STR2## or the pharmaceutically acceptable acid addition salts thereof; or the pharmaceutically acceptable base addition salts thereof;
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently:
(a) hydrogen; PA1 (b) C.sub.1 -C.sub.6 alkyl; PA1 (c) C.sub.1 -C.sub.6 alkoxy; PA1 (d) C.sub.2 -C.sub.6 hydroxyalkyl; PA1 (e) C.sub.1 -C.sub.4 fluorinated alkyl; or PA1 (f) halogen; and PA1 (a) hydrogen; or PA1 (b) C.sub.1 -C.sub.6 alkyl.
wherein R.sup.5 and R.sup.6 are independently:
Although the structure shown for Formula I indicates one tautomeric form, it is understood that this representation is for convenience only and that the scope of this invention includes as equivalents all tautomeric forms of the compounds of this invention.
The term "C.sub.1 -C.sub.6 alkyl" refers to straight or branched chain alkyl groups having from 1 to 6 carbon atoms, also referred to as lower alkyl. Examples of C.sub.1 -C.sub.6 alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, and the isomeric forms thereof.
The term "C.sub.1 -C.sub.6 alkoxy" refers to straight or branched chain alkoxy groups having from 1 to 6 carbon atoms. Examples of C.sub.1 -C.sub.6 alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the isomeric forms thereof.
The term "C.sub.2 -C.sub.6 hydroxyalkyl" refers to straight or branched chain hydroxyalkyl groups having from 2 to 6 carbon atoms. Examples of C.sub.2 -C.sub.6 hydroxyalkyl are 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl, and the isomeric forms thereof.
The term "C.sub.1 -C.sub.4 fluorinated alkyl" refers to straight or branched chain alkyl groups in which one or more hydrogen atoms are replaced with fluorine atoms. Examples of C.sub.1 -C.sub.4 fluorinated alkyl are fluoromethyl, difluoromethyl, trifluoromethyl, 1- or 2-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl; other similarly monofluorinated, polyfluorinated, and perfluorinated ethyl, propyl, and butyl groups; and the isomeric forms thereof.
Examples of halogen are fluorine, chloride, bromine, and iodine.
The term "pharmaceutically acceptable acid addition salt" refers to a salt prepared by contacting a compound of Formula I with an acid whose anion is generally considered suitable for human consumption. Examples of pharmacologically acceptable acid addition salts include the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, and tartrate salts.
The term "pharmaceutically acceptable base addition salt" refers to a salt prepared by contacting a compound of Formula I with a base whose cation is generally considered suitable for human consumption. Examples of pharmacologically acceptable base addition salts include lithium, sodium, potassium, magnesium, calcium, titanium, ammonium, alkylammonium, dialkylammomium, trialkylammonium, tetraalkylammonium, and guanidinium salts.
The compounds of this invention may be prepared by the methods illustrated in the following Schemes. Unless otherwise specified, the various substituents are defined as for Formula I, above. Scheme A illustrates the preparation of thio intermediates of Formula IV and of the sulfoxide compounds of this invention, Formula I.